Non-invasive ventilation (NIV) is currently a form of standard care for patients suffering from respiratory insufficiency, sleep apnea, chronic obstructive pulmonary disease (COPD) and more severe acute and chronic respiratory failure. Patients receiving NIV typically have underlying respiratory and systemic conditions that can be effectively treated with pharmaceutical aerosols. Administration of aerosol therapy simultaneously with NIV allows for continuous ventilation support. However, drug delivery efficiency to patients during NIV is very low (1-7% of the initial dose), resulting in high dose variability, increased side effects, and wasted medication. The objective of this study is to develop aerosol drug delivery systems that can significantly improve pulmonary drug deposition during NIV using a condensational growth approach. Three non-invasive ventilation techniques will be considered: (1) high-flow therapy (HFT) with heat and humidity using a cannula interface, (2) oxygen low-flow therapy (LFT) through a nasal cannula, and (3) non-invasive positive pressure ventilation (NPPV) through a face mask. The condensational growth concept begins with generating and delivering initially submicrometer aerosols (100 - 900 nm) to minimize deposition and loss in the delivery lines, patient interface, and extra thoracic airways. The aerosol is delivered with a saturated or supersaturated warm airstream and/or with the inclusion of hygroscopic excipients in order to foster condensational growth, leading to increased aerosol size and pulmonary deposition. Specifically, enhanced condensational growth (ECG) is achieved by combining the aerosol with a humidified airstream at the entrance to or within the airways, while enhanced excipient growth (EEG) consists of delivering combination drug and hygroscopic excipient submicrometer particles. Development and optimization of the aerosol delivery systems will be based on concurrent in vitro experiments and computational simulations in realistic models of the extra thoracic airways. In order to develop this novel respiratory drug delivery strategy, the following specific aims are proposed. Specific Aim 1: Develop an effective respiratory drug delivery system for use during nasal HFT based on enhanced condensational growth (ECG). Specific Aim 2: Develop an effective respiratory drug delivery technique for use with a low-flow nasal cannula oxygen system based on enhanced excipient growth (EEG). Specific Aim 3: Develop an effective respiratory drug delivery methodology for use with NPPV based on a combination of ECG and EEG. By delivering a submicrometer aerosol through the NIV system and extra thoracic nasal airways, and then increasing aerosol size with condensational growth, significant reductions in depositional losses are expected. As a result of using this concept, reduced variability in dose can be achieved together with near full lung retention, which is necessary for the effective use of many current and next-generation medical aerosols. PUBLIC HEALTH RELEVANCE: Patients receiving non-invasive ventilation (NIV) for respiratory support frequently need pharmaceutical aerosols to treat conditions like asthma, COPD, pulmonary hypertension, lung infections, and cystic fibrosis. However, 90% or more of the drug never reaches the patient's lungs due to deposition and loss in the NIV delivery system and nasal airways, which wastes potentially expensive medication and increases side effects. The overall goal of this project is to develop a novel technology for the efficient delivery of pharmaceutical aerosols during NIV that minimizes depositional losses in the delivery system and nasal airways and maximizes drug delivery to the lungs.